Project 1 Abstract In muscular dystrophies, such as Duchenne muscular dystrophy (DMD), in which there are ongoing bouts of degeneration followed by regeneration, muscle repair is achieved by activated muscle stem cells. Over time, fibrosis accumulates in the muscle, largely driven by increased TGF-?1, contributed by ongoing inflammation. Fibrosis itself is believed to contribute to failed regeneration, and as fibrosis accumulates regeneration is further depressed. Fibrosis can arise from a combination of cell types including resident fibroblasts, fibro-fatty precursor (FAP) cells, satellite cells themselves, and as we hypothesize in this proposal, from invading mesothelial precursor cells. Stem cells can also be directed into fat, creating a fibro-fatty matrix that gradually replaces the muscle cells. In this proposal, we will investigate the interaction betweens modulators of inflammation, fibrosis and cell fate to ultimately gain insight into the interplay of how these factors contributes to failed regeneration and how therapeutics can alter this process. The proposed studies will use a new, severe mouse model of Duchenne muscular dystrophy, the mdx mouse on the DBA background. The investigations are organized into three aims: (1) Delineation of the cells that contribute to fibrosis and fat; (2) Impact of genetic modifiers of inflammation and fibrosis on the cells involved in fibrosis; and (3) Modulation of fibrosis using therapeutics to decrease inflammatory and fibrotic responses and TGF-?1 signaling on the DBA background.